AAN: IVIG Treatment Slows Alzheimer's Decline

Action Points

Explain to interested patients that these results came from a small study and need to be confirmed in a larger trial.

Explain that IVIG is not FDA-approved for this indication and that other currently approved treatments can also slow cognitive decline in Alzheimer's disease, although they are not believed to affect brain atrophy.

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

In a small, 18-month study, patients treated with IVIG had a mean increase of just slightly more than five points from baseline in cognitive scores on the Alzheimer's Disease Assessment Scale, reflecting slight worsening, compared with a 15-point increase in patients who initially received placebo and were later switched to IVIG (P=0.013).

IVIG also appeared to reduce ventricular enlargement within patients' brains, a consequence of brain atrophy, Norman Relkin, MD, of Cornell Weill College of Medicine in New York City, reported at a poster session at the American Academy of Neurology meeting.

"This is the first Alzheimer's disease clinical trial to report a correlation between long-term treatment benefits and lower ventricular enlargement rates," he said.

The data confirmed preliminary results Relkin reported in 2008.

Those receiving IVIG for the full 18 months had a mean 46% reduction in growth of the ventricular space, according to Relkin.

Ventricular volume increased 12.3% per year in the initial placebo group, compared with 6.7% in patients receiving IVIG for 18 months (P=0.048).

The strength of this effect was significantly correlated with IVIG dose and also with changes in scores on the ADAS-Cog scale and the Clinical Global Impression of Change (CGIC), Relkin said.

Effects on the CGIC index were similar to those seen with ADAS-Cog. Over the 18-month study, a 1.36-point gap in CGIC scores opened between groups (P=0.011).

Scores on the Neuropsychiatric Inventory and Caregiver-Assessed Quality of Life ratings also showed more improvement with 18-month IVIG.

In a subsequent platform presentation at which Relkin presented more details of the efficacy results, he emphasized that the trial was designed as a so-called futility study, to determine if IVIG was worth studying further.

"This was not an efficacy trial, and we shouldn't put too much credence to these numbers," he said. "We started with a very small N [number of patients]."

The study involved 24 patients, with eight initially receiving placebo and 16 assigned to IVIG at doses ranging from 0.2 to 0.8 g/kg every two to four weeks.

After six months, patients in the placebo group were re-randomized to IVIG at the same range of doses.

Patients were evaluated every three months with the cognition tests and MRI scans.

Their mean age at baseline was about 72. More than half were carriers of the apoE epsilon-4 allele, which predisposes people to Alzheimer's disease.

At the poster session, Relkin reported strong correlations between the MRI measurements of ventricular enlargement and the CGIC and ADAS-Cog scores.

Relkin said the most effective dose appeared to be 0.4 g/kg given every two weeks. Aspects of cognition that appeared to benefit most strongly from the treatment included attention, working memory, and conceptualization.

Adverse effects occurring more often than expected with IVIG treatment included nonhemolytic anemia and rash, both of which were seen in 21% of patients.

No patients discontinued therapy because of adverse effects, Relkin said.

The rationale for IVIG is that it contains antibodies against beta-amyloid protein, which forms the sticky plaques that infest Alzheimer's patients' brains.

Relkin said the IVIG antibodies are polyclonal and include fibrils and oligomers among their targets, which could make them more effective than the monoclonal antibodies tested to date.

He said a separate study is under way, using positron emission tomography, to determine whether the treatment was reducing amyloid plaque loads.

One concern with IVIG is that it is produced from plasma donated by thousands of individuals who change over time. Relkin was unable to say whether lot-to-lot variability was significant in the study.

His team analyzed samples during the study to measure the content of specific anti-amyloid antibodies and these did not vary much, he said.

But he stressed that the antibodies that actually contribute to the observed effects in this and previous studies are not known.

Relkin said a 360-patient phase III study is now enrolling patients at 35 clinical sites in North America.

The manufacturer of the IVIG used in the study, Baxter, said it was also commencing a second phase III study to provide additional confirmation.

Another researcher not involved in the study urged caution for physicians and the public.

"The problem with this phase II data is that it's open label and there's no control group," said David Knopman, MD, of the Mayo Clinic in Rochester, Minn.

"I can give you example after example in the last few years of phase II results from anti-Alzheimer drugs that were very misleading," he said.

He added that the large differences Relkin reported between the patients who received IVIG for the full 18 months versus those on placebo for the first six months also posed an interpretation problem.

"I'm pleased that [the study results] are positive, but they're very difficult to interpret," said Knopman, who is a site investigator in the ongoing phase III study.

Relkin suggested the difference may have been an artifact of the study design. He noted that by the end of the six-month placebo period, those patients had already progressed to moderate-to-severe Alzheimer's disease.

Consequently, at that point, the groups were no longer matched, he said.

"It was not truly a delayed-start trial," he said.

Baxter and the National Institutes of Health supported the study.

Relkin and Knopman reported research funding from Baxter. No other potential conflicts of interest were declared.

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